Positive feedback of G1 cyclins ensures coherent cell cycle entry

Nature. 2008 Jul 17;454(7202):291-6. doi: 10.1038/nature07118.

Abstract

In budding yeast, Saccharomyces cerevisiae, the Start checkpoint integrates multiple internal and external signals into an all-or-none decision to enter the cell cycle. Here we show that Start behaves like a switch due to systems-level feedback in the regulatory network. In contrast to current models proposing a linear cascade of Start activation, transcriptional positive feedback of the G1 cyclins Cln1 and Cln2 induces the near-simultaneous expression of the approximately 200-gene G1/S regulon. Nuclear Cln2 drives coherent regulon expression, whereas cytoplasmic Cln2 drives efficient budding. Cells with the CLN1 and CLN2 genes deleted frequently arrest as unbudded cells, incurring a large fluctuation-induced fitness penalty due to both the lack of cytoplasmic Cln2 and insufficient G1/S regulon expression. Thus, positive-feedback-amplified expression of Cln1 and Cln2 simultaneously drives robust budding and rapid, coherent regulon expression. A similar G1/S regulatory network in mammalian cells, comprised of non-orthologous genes, suggests either conservation of regulatory architecture or convergent evolution.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Cycle / physiology*
  • Cyclins / genetics
  • Cyclins / metabolism*
  • Feedback, Physiological*
  • G1 Phase*
  • Gene Expression Regulation, Fungal
  • Mitosis
  • Phosphorylation
  • Regulon / genetics
  • Repressor Proteins / metabolism
  • Saccharomyces cerevisiae / cytology*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism
  • Sequence Deletion
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • CLN1 protein, S cerevisiae
  • CLN2 protein, S cerevisiae
  • Cyclins
  • MBP1 protein, S cerevisiae
  • Repressor Proteins
  • SBF protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Transcription Factors
  • Whi5 protein, S cerevisiae